DESCRIPTION: A major obstacle to cure HIV infection is our incomplete understanding of what factors regulate the immunologic response to antiretroviral therapy (ART) and the establishment and persistence of the latent HIV reservoir. Although it is well established that HIV preferentiall infects memory CD4 T cells, it is still unclear whether and to what extent the relative distributio of HIV infection within the various CD4 T cell subsets influences: (i) the magnitude of CD4 T cell reconstitution, (ii) the extent of residual immune activation/inflammation and (iii) the size of th persistent HIV reservoir during ART. These questions are highly relevant to people living with HIV (PLHIV) because targeting specific CD4 T cell subsets could be a potential priority to cure HIV infection. CD4 Central Memory T cells (TCM) are long-lived, self-renewing cells with a crucial role for CD4 T cell homeostasis and overall immune function. Recent evidence generated in nonhuman primate models of HIV infection implicates the infection of CD4 TCM as a key factor determining the outcome of infection. In the pathogenic SIV-infection of rhesus macaques, the levels of infection and depletion of CD4 TCM dictate the tempo of progression to AIDS, and the preservation of CD4 TCM in vaccinated animals associates with resistance to SIV infection. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, a low level of CD4 TCM infection is a key mechanism of AIDS resistance. Consistent with the importance of preserving TCM from infection and with the findings that TCM have a longer half-life than TEM, we showed that in PLHIV on ART CD4 TCM represent the largest reservoir of infected CD4 T cells. Based on these findings, we propose a novel, paradigm-shifting model according to which the pattern of infected CD4 T cells is more important than the overall level of immune activation, virus replication, and the total number of infected cells in dictating the magnitude of CD4 T cell reconstitution and the size of the virus reservoir during ART. Here, we will test the hypotheses that, in blood and lymph nodes, CD4 TCM infection (i) critically contributes to the extent of immunologic restoration and residual immune activation [Aim 1] and (ii) is a prognostic factor for both the size and stability of the HIV reservoir [Aim 2] following ART. In addition, we are proposing a series of mechanistic studies aimed at defining the molecular correlates of CD4 TCM infection and designing therapeutic intervention that can protect these cells from infection [Aim 3]. We believe the proposed research is highly relevant to human health. By testing a radically innovative hypothesis, these studies will provide unprecedented, novel insights into the mechanism underlying the quality of the immunological response to ART and the resulting size/persistence of the HIV reservoir in PLHIV. If our hypothesis is confirmed, these studies will suggest that novel strategies aimed at protecting CD4 TCM from infection should be a critical component of interventions aimed at curing HIV infection.